The development of insulin-dependent diabetes mellitus (IDDM) results from the almost total destruction of insulin-producing pancreatic beta cells by beta cell-specific autoimmune responses. The cure of IDDM has long been attempted using methods such as islet transplantation, regeneration of beta cells and insulin gene therapy. However, permanent remission of IDDM has not yet been satisfactorily achieved. We recently developed a recombinant adeno-associated virus (rAAV) that expresses a single chain insulin analog (SIA), which possesses biologically active insulin activity without processing, under the control of the hepatocyte-specific L-type pyruvate kinase promoter (rAAV-LPK-SIA), which regulates SIA expression in response to blood glucose levels. Intraportal venous injection of rAAV-LPK-SIA resulted in the long-term remission of diabetes in streptozotocin (STZ)-induced diabetic rats and nonobese diabetic mice without any apparent side-effects. However, a painful and potentially risky surgical procedure involving a mid-line abdominal incision was required for the delivery of rAAV-LPK-SIA to the liver. The first Specific Aim of this study is to improve this novel gene therapy by replacing the surgical procedure with a simple intravenous injection that does not require surgery. The non-human primate is an ideal model to test this rAAV-LPK-SIA gene therapy for preclinical trials, as they are physiologically and morphologically similar to humans. The common marmoset (Callithrix jacchus) is a non-human primate that is relatively small, inexpensive and easy to handle and breed as compared to other non-human primates. The second Specific Aim of this study is to determine whether the administration of rAAV-LPK-SIA into the STZ-induced diabetic marmoset can express SIA and control blood glucose levels, resulting in the long-term remission of diabetes. The information obtained through these studies will be invaluable for the development of a gene therapy for the cure of human type 1 diabetes.